Keywords

Introduction

Anemia is one of the most common problems in children with chronic kidney disease (CKD); it is almost universal in children with stage 5 CKD. The development of recombinant human erythropoietin (rHuEPO) revolutionized the treatment of anemia in CKD, but anemia management remains challenging. Many management issues remain uncertain, including the ideal target hemoglobin (Hb). There are guidelines for the management of anemia in CKD [1,2,3].

Pathophysiology of Anemia

A variety of factors contribute to anemia in CKD (Table 59.1). The principal etiology is decreased production of EPO by the kidneys. However, many children are still anemic despite administration of erythropoiesis stimulating agents (ESAs) [4, 5], emphasizing the multifactorial etiology of anemia in children with CKD.

Table 59.1 Causes of anemia in CKD
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Erythropoietin Deficiency

The kidneys produce EPO and kidney damage leads to decreased EPO production. In children with CKD, EPO levels are inappropriately low for the degree of anemia [6]. The degree of EPO deficiency generally worsens as the glomerular filtration rate (GFR) decreases, but the level of GFR at which inadequate EPO causes anemia varies between patients, partially due to the nature of the underlying kidney disease [7]. On average, a GFR below 43 mL/min/1.73 m2 is associated with a decline in Hb in children with CKD [8].

Blood Loss

Excessive blood loss may directly cause anemia, or it may lead to iron deficiency (see below). Causes of blood loss in children with CKD include phlebotomy, blood lost in the dialyzer and tubing during hemodialysis (HD) [9], gastrointestinal losses [9], and increased menstrual bleeding due to the acquired platelet function defect of CKD. Children receiving HD have increased intestinal blood loss when compared to other children with CKD [9] and have lower Hb values than children receiving peritoneal dialysis (PD) [5]. Increased blood loss is associated with rHuEPO resistance in pediatric HD patients [10].

Decreased Red Blood Cell Survival

Red blood cells in children with CKD have a decreased lifespan [9]. This may be partially due to carnitine deficiency (see below) [11], and a direct consequence of EPO deficiency, since red cell survival increases in CKD patients after starting rHuEPO [12]. Red blood cells in patients receiving HD have an increased osmotic fragility. Hemolytic anemia may occur due to a child’s primary disease [e.g. systemic lupus erythematosus (SLE)].

Bone Marrow Suppression

In an in vitro assay, serum from children with CKD directly suppressed red blood cell production [6]. The specific inhibitory substances have not been identified, but dialysis appears to effectively remove some of these molecules, allowing for decreased doses of rHuEPO [13]. In a study of teenagers receiving HD, the children with Hb less than 11 g/dL had a slightly lower Kt/Vurea (1.46 v.s 1.53), but dialysis adequacy did not predict anemia in the multiple regression analysis, perhaps due to the high overall Kt/V in this patient population [14]. Severe bone marrow suppression may occur in children after renal transplantation due to medications [15] or infections, especially parvovirus B19 [16].

Iron Deficiency

Iron deficiency is a significant cause of anemia in patients with CKD; it is multifactorial (Table 59.2). In a study of older children, a serum transferrin saturation (TSAT) less than 20% was an independent predictor of anemia [14]. However, serum ferritin was not predictive of anemia, perhaps because ferritin is often elevated in CKD patients with concurrent inflammation, which may inhibit red cell synthesis (see below). This is supported by a study of children receiving PD where Hb was inversely related to serum ferritin [17].

Table 59.2 Causes of iron deficiency in children with CKD
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Iron deficiency often develops after initiation of an ESA because the increase in red blood cell synthesis depletes iron stores. In some patients, there is a functional iron deficiency following ESA treatment; there are adequate supplies of iron, but the transfer of iron from ferritin is not fast enough to meet the high demand for red blood cell synthesis.

Inadequate Dialysis

In adults receiving dialysis, there is evidence that anemia is associated with inadequate dialysis. An increase in dialysis dose leads to an improvement in Hb. In addition, there is an inverse relationship between Kt/V and ESA dose. Resistance to ESAs was associated with a lower Kt/V in a study of pediatric HD patients [10]. Dialysis is effective at removing hepcidin (see below) [18], suggesting a possible mechanism for the relationship between dialysis dose and anemia.

Malnutrition

Malnutrition may be another factor contributing to anemia in CKD. In one pediatric study, low albumin was one predictor of anemia [14]. There are many possible explanations for the relationship between malnutrition and anemia. Generalized malnutrition may be a marker for nutritional iron deficiency or for deficiency of other nutrients that influence red cell production or survival. Another possible explanation for this observation is the relationship between markers of malnutrition and markers of inflammation [19]. As described below, inflammation is another mechanism of resistance to rHuEPO. It is possible that inflammation causes malnutrition, and this directly causes resistance to ESAs. An alternative explanation is that inflammation directly causes rHuEPO resistance, and that malnutrition is a surrogate marker of inflammation. A malnutrition inflammation score predicted ESA resistance in a study of pediatric HD patients [10].

Inflammation

Acute and chronic inflammation are well-known causes of decreased red blood cell synthesis. Inflammation is one of the mechanisms of the anemia of chronic disease and of the decreased erythropoiesis that occurs during infections. Markers of inflammation are commonly increased in CKD patients. There are a variety of putative mechanisms. Surgical procedures and acute infections are more common in CKD patients, especially those who are receiving dialysis or have a kidney transplant. The impaired immune system in uremia may lead to an increase in non-specific inflammation [20]. CKD patients may have underlying systemic diseases, such as SLE or granulomatosis with polyangiitis. HD may induce inflammation via complement activation, direct activation of inflammatory cells by the dialysis membrane, and diffusion of endotoxin into the patient from the dialysate. Use of ultrapure dialysis in HD patients decreases inflammatory markers, increases Hb levels, and decreases ESA use [21].

Hepcidin is an important mediator of ESA resistance [22]. Hepcidin, which is produced in the liver, inhibits intestinal absorption of iron and release of iron stores from the reticuloendothelial system. This is accomplished through down-regulation of ferroprotein, the principal transmembrane transporter of iron. Hepcidin is normally down-regulated in anemia, increasing absorption of iron and release of iron stores. In contrast, hepcidin increases when iron stores are adequate. Hepcidin is also up-regulated by inflammation. Interleukin 6 (IL-6) induces production of hepcidin and is risk factor for ESA resistance [23, 24]. Hepcidin’s effect on release of iron stores explains inflammatory block, a condition where body stores of iron are adequate, but there is ineffective delivery of iron to the bone marrow. Findings in patients with inflammatory blockade may include elevated C-reactive protein (CRP) levels, resistance to ESAs, high serum ferritin levels, and low levels of serum iron and TSAT [25]. This mechanism is common to the anemia of many chronic diseases.

Hyperparathyroidism

Hyperparathyroidism may decrease bone marrow production of red blood cells [26] and rarely causes pancytopenia [27]. Elevated parathyroid hormone (PTH) levels are associated with ESA resistance in pediatric HD patients [10] and PTH is inversely related to Hb in pediatric dialysis patients [5]. Treatment of hyperparathyroidism via parathyroidectomy may lead to an increase in Hb.

B12 or Folate Deficiency

Patients with CKD may rarely develop a megaloblastic anemia due to folate or vitamin B12 deficiency. Poor nutritional intake combined with dialytic losses may predispose CKD patients to deficiencies of these water-soluble vitamins. There is some evidence that routine folate supplementation improves the response to rHuEPO, even in the absence of low serum levels of folic acid [28].

Aluminum Toxicity

Aluminum overload may cause a microcytic anemia in patients with CKD [29]. Currently, aluminum overload is an uncommon cause of anemia due to the recognition of the dangers of aluminum-containing phosphate binders.

Carnitine Deficiency

Carnitine deficiency may occur in CKD, principally due to removal of carnitine by dialysis, although decreased dietary intake and endogenous synthesis may also contribute [11]. Renal losses of carnitine are significant in children with Fanconi syndrome. Carnitine deficiency may decrease red blood cell survival by reducing the strength of the red cell membrane [11]. Intravenous (IV) carnitine may reduce rHuEPO dose requirements in adults receiving HD, but there is disagreement regarding the strength of the evidence; carnitine should not be used routinely in children, if at all, outside of a research setting [1, 11, 30,31,32]. Oral carnitine should not be used in patients receiving HD [11].

Medications

A variety of medications can inhibit erythropoiesis, especially certain medications used in renal transplant recipients [15, 33]. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are especially pertinent in CKD patients because of their widespread use [34].

Summary

Erythropoietin deficiency and iron deficiency are the most common causes of anemia in children with CKD. Inflammation and hyperparathyroidism are important mediators of ESA resistance.

Epidemiology of Anemia in Pediatric CKD

Anemia is common in children with CKD, even in patients with stage 3 CKD [5, 35]. In one study, anemia was more common in children greater than 2 years old, males, and patients receiving antihypertensive medications [35]. In another cohort, African American race was associated with an increased risk of anemia in children with CKD [4].

In children receiving PD, anemia is quite common and varies by region [17]. Risk factors for anemia include inflammation, decreased residual urine output and hyperparathyroidism [17].

Anemia is common in children after kidney transplantation [36]. The principal cause of anemia is allograft dysfunction, although current immunosuppressive medications appear to be responsible for the increased prevalence of anemia in these patients. Iron deficiency is common in children who are anemic after renal transplantation.

Clinical Effects of Anemia

There are a variety of clinical effects of anemia (Table 59.3). The clinical consequences of anemia in patients with CKD are difficult to discern because anemia identifies patients with co-morbidities such as inflammation and malnutrition. A variety of studies demonstrated an association between anemia and morbidity and mortality, but these conclusions may be biased by co-morbidities.

Table 59.3 Clinical effects of anemia
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Studies in adult CKD patients have shown an association between anemia and increased mortality and hospitalization rates [37,38,39,40]. In a pediatric analysis, anemia 30 days after initiation of dialysis was associated with a significant increase in mortality and hospitalization rate [41]. In analysis of children receiving PD, anemia was associated with increased mortality, hypertension, and left ventricular hypertrophy (LVH) [17], suggesting that in patients with ESKD low Hb may partially reflect fluid overload (“dilutional anemia”). In children with CKD, anemia was associated with an increased risk of hospitalization [42].

In a group of children receiving dialysis, treatment of anemia with rHuEPO was associated with an elevated cardiac index in 6 months and a significant reduction in left ventricular mass index by 12 months [43]. In one study [44], children with severe LVH had significantly lower Hb values than children without LVH. However, anemia did not predict LVH in the final multiple regression model.

There is uncertainty regarding the direct deleterious consequences of a lower Hb in adults with CKD. These include observational studies that have corrected for a variety of co-morbidities [45]. More importantly, randomized studies using ESAs to target different Hb levels have failed to demonstrate a benefit of higher Hb targets on morbidity or mortality [46, 47]. In fact, a higher Hb target has resulted in a significant increase in morbidity and mortality in randomized studies [48, 49].

In randomized studies in adults, a higher Hb improves quality of life [47], although this is not a consistent finding [48, 50]. In a placebo-controlled trial, randomization to rHuEPO resulted in less fatigue, improved exercise tolerance and improved scores of physical symptoms and depression [51]. There is evidence of the deleterious effects of anemia on child development. There is an association in children with CKD between anemia and lower scores of health-related quality of life [52]. Studies of the effect of rHuEPO in children with CKD have shown improvement in quality of life, exercise tolerance, appetite, peak oxygen consumption and treadmill time during exercise testing, Wechsler intelligence score, and ventilatory aerobic threshold [53,54,55]. There does not appear to be a beneficial effect of anemia correction on the growth retardation associated with CKD [56].

Clinical Evaluation of Anemia

Initial Evaluation

Alternative causes of anemia should be evaluated prior to treating patients with an ESA (Table 59.4). The diagnosis of anemia in children should be based on age and gender specific normal ranges.

Table 59.4 Indications for additional evaluation in children with chronic kidney disease and anemia
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The initial evaluation of children with CKD and anemia should include a complete blood count, reticulocyte count, ferritin, iron, total iron binding capacity (TIBC) and a TSAT. The TSAT is calculated by dividing the serum iron by the TIBC. Measurement of EPO levels generally does not have clinical utility. A cost-effectiveness analysis in adults argues against routine screening for aluminum overload or deficiencies of folate or B12 [57]. EPO deficiency causes a normocytic anemia; macrocytosis or microcytosis should lead to consideration of other etiologies (Table 59.4).

A low mean corpuscular volume (MCV) occurs with iron deficiency, thalassemia and in up to 50% of patients with anemia of chronic disease. A high MCV suggests the possibility of B12 or folate deficiency. Measurement of serum levels of B12 and folate is indicated if there is an elevated MCV or if there is anemia without an alternative explanation. RBC folate is useful when a serum folate level is inconclusive or if recent intake of folate may lead to a falsely normal serum folate level.

Concomitant depression of white cells or platelets raises the specter of malignancy, although an isolated low white blood cell count may be due to a transient viral infection or a medication. SLE may cause depression of the white blood cell count, platelet count and an autoimmune Coombs positive hemolytic anemia. EPO deficiency causes an inappropriately low reticulocyte count, and the presence of an adequate reticulocytosis suggests alternative explanations, such as blood loss or hemolysis. An elevated CRP, indicating inflammation, may provide an explanation for anemia refractory to ESAs.

Iron deficiency is common in children with CKD, even prior to starting an ESA. There are a variety of explanations for iron deficiency in children with CKD (Table 59.2). All children with CKD should be queried about gastrointestinal blood loss and, when appropriate, menstrual losses. A more aggressive work-up (e.g. testing stool for occult blood or endoscopy) is appropriate in children with significant, unexplained iron deficiency prior to receiving ESA therapy. Along with low serum ferritin and TSAT, children with iron deficiency typically have a low MCV. Because it is a marker of inflammation, serum ferritin may be misleadingly normal in children with CKD despite iron deficiency.

Evaluation of the ferritin and TSAT establishes a baseline, since iron deficiency is likely to develop during ESA treatment. In addition, while all patients starting an ESA should receive oral iron supplementation unless iron overload is present, iron deficiency prior to starting ESA therapy may significantly attenuate the response to therapy. Such patients are candidates for IV iron.

Chronic Monitoring

Routine monitoring in children with anemia due to CKD includes periodic assessment of Hb, MCV, and iron stores. The development of macrocytosis in a patient after starting an ESA is usually due to the expected reticulocytosis; an increasing Hb, arguing against a nutritional deficiency anemia, supports this explanation. Iron overload may also cause an increased MCV [58]. Microcytosis is usually due to iron deficiency.

A decrease in Hb is expected during acute infections [59] or after surgical procedures [60]. ESA dose requirements increase following blood loss that causes a fall in Hb; this persists until the Hb returns to the target range. Depleted iron stores are the usual explanation for a poor response to ESA therapy. Some children have a functional iron deficiency, and may respond to IV iron, even though the ferritin levels are adequate. Additional evaluation is indicated in children who have an unexplained increase in ESA dose requirement, need unexpectedly large doses of ESA, or have a decreasing Hb (Table 59.4).

A reticulocyte count is the usual first step in evaluating unexplained anemia or an excessive ESA requirement. An appropriately elevated reticulocyte count (corrected for the degree of anemia) argues that the patient is anemic due to blood loss or hemolysis. Blood loss is also suggested by a minimal increase in ferritin and TSAT despite the use of multiple doses of IV iron. The child should then have stool tested for occult blood; an evaluation for hemolysis may also be appropriate. Inadequate reticulocytosis suggests that there is a defect in red cell production. This may be due to poor adherence or technique failure in a patient receiving home ESA. There may be a readily identifiable explanation, such as severe secondary hyperparathyroidism. Alternatively, additional testing may be necessary. A serum aluminum level is an appropriate test in the child with a history of using aluminum-containing phosphate binders. One of the most common causes of a poor response to ESA is an inflammatory block due to acute or chronic inflammation. An elevated CRP supports this diagnosis [20]. Other testing, depending on the patient, may include screening for anti-EPO antibodies (see below), and serum levels of folate and B12. A hematologist should evaluate refractory anemia with no identifiable explanation [31, 61].

Treatment of Anemia

Treatment with an ESA is necessary in many children with CKD, including children with chronic allograft dysfunction [62]. Almost all children receiving dialysis are treated with an ESA. In addition, almost all treated patients require oral or IV iron. Other underlying causes of anemia should be corrected (Table 59.1). Blood transfusions should be reserved for children with symptomatic anemia or with worsening anemia due to blood loss, hemolysis, or unresponsiveness to ESAs [1].

Target Hemoglobin

A number of randomized studies in adult patients with CKD have demonstrated that targeting higher Hb levels leads to increased morbidity and mortality [46, 48, 49, 63]. In one study, targeting a higher Hb led to a decrease in dialysis adequacy and a higher use of IV iron [46]. The TREAT trial compared placebo and darbepoetin alpha (DA) in adults with CKD. The risk of stroke was almost doubled in the patients randomized to receive DA to achieve a Hb of 13 g/dL, although there was a modest improvement in fatigue in the DA group [49]. Stroke was also increased when adult HD patients were randomized to a higher Hb target [63]. In the CREATE trial, the group randomized to a higher Hb had more episodes of hypertension and headache [47]. In the CHOIR trial, the group randomized to a higher Hb had an increased risk of death or cardiovascular event and there was no difference in quality of life between the groups [48]. In a retrospective cohort study of adult kidney transplant recipients, patients receiving an ESA with a Hb level above 12.5 g/dL had an increase in mortality [64].

The reason for the increased morbidity and mortality associated with a higher Hb target is unresolved. It could be attributed to a higher Hb level or to the need for higher doses of ESAs, which have been postulated to have untoward effects beyond increasing the Hb. High ESA dose is associated with increased morbidity and mortality, but this appears to be partially related to resistance to ESAs due to co-morbidities [65,66,67]. However, in studies that randomized CKD patients to ESA or placebo, the groups receiving ESAs had an increased risk of stroke [49] and access clotting [51]. Moreover, in a randomized study of rHuEPO in patients with ischemic stroke, the group receiving rHuEPO had significantly increased mortality [68]. Dialysis patients who have high Hb levels without the use of ESAs do not have increased mortality [69]. A higher Hb target could lead to more variation in Hb levels, which has been associated with increased mortality [70].

The negative consequences of targeting higher Hb concentrations in the trials of ESAs has led the US Food and Drug Administration (FDA) to recommend that ESAs be given at the lowest dose possible to avoid blood transfusions and that ESAs should be reduced or withheld if the Hb exceeds 11 g/dL and withheld if the Hb exceeds 12 g/dL. Moreover, all ESAs have a black box warning and patients must receive education regarding the possible adverse effects of ESAs. A combination of these concerns, and possibly a change in the payment structure for ESAs, has led to a decrease in the dose of ESAs and Hb levels in US dialysis patients [71].

There are no data on the ideal target Hb in children or whether the target should be adjusted based on age and gender. Kidney Disease: Improving Global Outcomes (KDIGO) recommends an upper limit Hb of 11.5 g/dL in adults, but recommends targeting pediatric CKD patients between 11–12 g/dL. The British NICE guidelines recommend a target of 10–12 g/dL for all patient 2 years and older, with a target of 9.5–11.5 g/dL in children less than 2 years [2, 3]. The Canadian Society of Nephrology recommends a target of 10–11 g/dL for adults, but considers 9.5–11.5 g/dL an acceptable range [72]. The US KDOQI commentary on KDIGO advocates the FDA-recommended upper cutoff of 11 g/dL for adults, but a range of 11–13 g/dL for children [73]. There are clearly clinical situations that require different target Hb values. For example, specific children may require a higher target Hb (e.g. a child with underlying cyanotic heart disease) or a lower target (e.g. a child with sickle cell disease).

Some patients remain anemic or develop refractory anemia despite ESA therapy and correction of other etiologies of anemia. This is especially common in patients who have inflammation. Ongoing escalation of ESA dose in these patients has been associated with adverse outcomes in adults [49], suggesting that ESA dose should not be increased without limit in patients who are hyporesponsive. Patients who do not respond to an ESA or stop responding to an ESA should have an evaluation of possible etiologies of anemia (Tables 56.1 and 56.4).

Hemoglobin Monitoring

Hb monitoring is preferred over hematocrit because Hb measurements are more standardized and consistent. For patients receiving HD, blood samples should be taken immediately prior to dialysis. This may lead to a falsely low Hb value due to hemodilution from fluid gain between dialysis sessions. Hence, this should be considered in children with significant interdialytic weight gain. It is reasonable to measure Hb prior to a HD session after a short interdialytic period (2 days) since the effect of hemodilution on Hb is generally less significant [31].

The frequency of monitoring varies depending on the patient. Children who are being given a stable dose of ESA and within their target Hb can have a Hb level performed as infrequently as monthly in a dialysis patient, and even less often in a predialysis patient (minimum of every 3 months). After the initiation of ESA or after a dosing change, a Hb should generally be obtained at least monthly until the Hb has stabilized within the target range. Protocols that use less frequent monitoring and dose adjustments may reduce costs and minimize Hb cycling, large variations in Hb values that are associated with increased morbidity in adults [74, 75].

Erythropoiesis Stimulating Agents

rHuEPO was the first ESA, but a number of other preparations are now available. Two preparations, DA and methoxy polyethylene glycol (PEG)-epoetin beta, are modified forms of EPO. The main advantage of other preparations is a longer half-life, which permits less frequent dosing. This is especially advantageous in children who require subcutaneous dosing given the discomfort and fear associated with injections. Less frequent dosing may also decrease provider burden in a dialysis unit and provide cost savings [76]. Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHIs) have a different mechanism of action than the other ESAs, including both stimulation of EPO production and increasing iron bioavailability. HIH-PHIs have the advantage of oral administration, but regulatory approval has been slow due to safety concerns; they have not been systematically studied in children.

There are no studies directly comparing different ESAs in children, and limited studies in adults except for comparisons of the HIF-PHIs with other ESAs. Availability of the different preparations varies by country.

Recombinant Human Erythropoietin

Multiple studies in adult patients demonstrated the efficacy of IV and subcutaneously administered rHuEPO for correcting the anemia of CKD. A placebo controlled trial demonstrated that rHuEPO is effective in children with CKD [55], and studies in adults demonstrate that use of ESAs decreases the need for transfusions [49, 51, 77].

Pharmacokinetics

The pharmacokinetics of rHuEPO in CKD has been studied in children and adults. There are clear differences based on the route of administration, with less complete absorption of subcutaneous rHuEPO, but a significantly longer half-life when compared to IV administration. In studies of children with CKD, the measured mean half-life of rHuEPO is 5.6–7.5 h for IV dosing and 14.2–25.2 h for subcutaneous dosing. For IV dosing, there is evidence in adults that the half-life of rHuEPO increases as the dose increases.

Dosing

There are dramatic differences in the dosing needs of children with CKD who are receiving rHuEPO, even when adjusted for patient size [78, 79]. Some have recommended dosing children independent of weight and utilizing “adult” dosing [80]. A variety of variables influence the dosing needs of patients (Table 59.5), but it remains difficult to predict the dosing needs of an individual patient. Factors affecting the necessary dose per kilogram (kg) of rHuEPO in children with CKD include the stage of CKD (higher in stage 5), the mode of dialysis (higher in HD due to increased blood loss) [81, 82], the age of the patient (higher in younger patients) [78, 79, 82], the route of administration (higher with IV versus subcutaneous) [79], and the dosing frequency (higher with less frequent dosing regimens). Concurrent causes of poor response to rHuEPO, such as iron deficiency, inflammation, or hyperparathyroidism, often result in higher doses. Blood loss, due to HD, blood draws, and other sources, increase the need for rHuEPO. Blood draws can be especially problematic in the youngest patients, because they often need more frequent monitoring and the relative losses per kg of body weight tend to be higher. Finally, residual renal production of EPO can decrease the need for rHuEPO.

Table 59.5 Factors influencing erythropoietin dosing
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In children receiving PD or predialysis patients, an appropriate starting dose for subcutaneous rHuEPO is 100 units/kg/week divided into two doses, although once weekly dosing may be appropriate in a child with mild anemia. Children less than 5 years are likely to need a higher dose, and a starting dose of 150 units/kg/week may be appropriate in such patients, especially if severe anemia (Hb < 8 g/dL) is present. Alternatively, a study of children receiving PD demonstrated that the average weekly dose of EPO was 4300 IU/m2 independent of age [17], suggesting that body surface area can be used to dose EPO in children independent of age or weight. For children receiving HD and IV rHuEPO dosing, a starting dose of 150 units/kg/week divided into theree doses is reasonable, again with the caveat that higher doses are likely necessary in children less than 5 years. A starting dose of 200–300 units/kg/week may be more appropriate in such patients, especially if there is concomitant severe anemia.

In children receiving chronic subcutaneous dosing of rHuEPO, the majority can be maintained on weekly dosing to minimize the number of painful injections. However, some patients require more frequent injections. Less frequent dosing regimens of rHuEPO are effective in adults with pre-dialysis CKD [83].

When children receive IV dosing during HD, it is important to inject rHuEPO via the bloodlines. Use of the venous drip chamber may result in reduced drug delivery due to “trapping” of rHuEPO, although this appears to be somewhat machine dependent.

For children receiving subcutaneous dosing, the site of injection should be rotated. The discomfort of subcutaneous dosing can be reduced by utilizing the multidose vial, which contains the local anesthetic benzyl alcohol as a preservative.

Frequent dose adjustments are typically necessary in patients receiving rHuEPO. This is probably due to variations in the factors that cause anemia (Table 59.1) and that influence rHuEPO dosing (Table 59.5). In addition, more active erythropoiesis is needed to increase a patient’s Hb. Hence, the dose that patients need to increase their Hb level into the target range is often more than the dose needed to maintain a stable Hb. Patients may need higher doses of rHuEPO at the start of therapy or after a decrease in Hb due to blood loss or a transient illness.

Most children, when they initiate HD, are converted to IV dosing of rHuEPO, which should then almost always be given thrice weekly. Based on adult studies, the total weekly dose of rHuEPO should be increased by 50% when a patient changes from subcutaneous to IV dosing. Similarly, patients changing from IV dosing to subcutaneous dosing should have their weekly dose decreased by 33%. However, most pediatric patients who convert between IV and subcutaneous dosing are also changing dialysis modality. Given the higher needs for rHuEPO in children on HD [78], patients changing to IV dosing because they are initiating HD may need an additional increase in their dose. In children less than 10 years and certainly those less than 5 years, rHuEPO dosing requirements during HD are very high [79]. This suggests that these patients may need an increase in their rHuEPO dose after beginning HD, irrespective of any change in route of administration. Young children should have careful monitoring of the Hb when initiating HD, increasing the dose of rHuEPO further if necessary. Even in older children, there is extreme variability in the dose requirements when converting to IV dosing; dose requirements may increase or decrease. The ability to more aggressively treat iron deficiency in children receiving HD (see below) may result in a decrease in rHuEPO requirements.

The goal of rHuEPO therapy is to maintain patient Hb within a desired target range. Overly rapid increases in Hb can be associated with hypertension, and should be avoided. In patients with a Hb below the target, the goal is to increase the Hb by 1–2 g/dL per month. The dose of rHuEPO should be increased by 25% if the patient is below the target Hb and has not increased at least 1 g/dL over the last month. The dose should be reduced by 25% if the Hb is greater than the target Hb or the Hb has increased by more than 2 g/dL over the last month. The rHuEPO should be temporarily held if the Hb is more than 1 g/dL over the target Hb or the Hb has increased by more than 2 g/dL over the last month and is above the target Hb.

Complications

An increase in blood pressure after starting rHuEPO therapy may occur in children [55, 84]. This appears to be more common in children who receive higher doses of rHuEPO, and have a consequent more rapid increase in Hb [85]. Hence, rapid increases in Hb should be avoided. While the increase in red cell mass appears to be one mechanism of the hypertension, there also appears to be a direct effect of rHuEPO on the vasculature.

An increase in vascular access clotting following rHuEPO treatment has been attributed to the increase in Hb. There may also be a small negative effect on dialytic clearance, but this is not clinically significant.

Iron deficiency may develop in children treated with rHuEPO [55, 84]. This is secondary to iron utilization for red blood cell synthesis. Consequently, unless iron overload is present, all patients treated with rHuEPO should receive iron supplementation and be screened for iron deficiency before and during therapy.

A rare complication of rHuEPO is the development of anti-EPO antibodies [86]. These antibodies neutralize both endogenous EPO and rHuEPO, resulting in red cell aplasia. Immunosuppressive therapy, including after renal transplantation, results in hematologic recovery in many patients [87]. Patients with undetectable anti-EPO antibodies may subsequently respond to rHuEPO [87].

Darbepoetin Alpha

DA (Aranesp™) is a genetically engineered molecule with a longer half-life than rHuEPO, permitting less frequent administration. The longer half-life of DA is due two additional N-glycosylation sites.

Efficacy

Studies in adults demonstrate comparable efficacy of rHuEPO and DA, despite less frequent dosing of DA [88, 89]. One study demonstrated that many CKD patients do well when receiving DA subcutaneously as infrequently as once every 3–4 weeks [90].

In a prospective study, children receiving rHuEPO were randomized to rHuEPO or DA at a less frequent dosing interval (0.42 μg of DA per week for each 100 units/week of rHuEPO). There was no significant difference in Hb or side effects between the groups at the end of the 20-week study; the median weekly dose of DA was 0.41 mcg/kg, with 25th and 75th percentiles of 0.25 and 0.82 mcg/kg, respectively [91]. A small prospective study evaluated the response to converting seven children receiving HD from thrice weekly rHuEPO to weekly DA (1 mcg of DA per week for each 200 units/week of rHuEPO). Especially in the younger children who were receiving high doses of rHuEPO, there were problems initially with elevated Hb levels and associated hypertension. This was corrected by reducing the dose of DA, suggesting that this dose conversion ratio may be inappropriate in younger children, and that careful monitoring of the initial response is necessary when converting to DA. The mean steady-state dose of DA after 3 months was 0.51 mcg/kg/week [92].

In a large prospective study, children with CKD and anemia were given DA at a starting dose of 0.45 μg/kg/week. There was a significant improvement in Hb and it was sustained during the 28 weeks of the study. By the end of the study, slightly more than half the patients were receiving DA at dosing intervals of at least 2 weeks [93]. A small study has described the successful use of DA in infants, with a starting dose of 0.5 μg/kg/week [94]. The dose was able to be reduced and the dosing interval was increased to 3–4 weeks in some of the infants [94]. In another study in children, the initial dose in naïve patients was 0.45 mcg/kg and patients previously treated with rHuEPO were converted using a dose of 1 mcg of DA per 200 IU of rHuEPO [95]. The final dose was higher in the patients converted from rHuEPO, perhaps because most of these patients were receiving dialysis and none of the naïve patients were dialysis patients [95]. In a prospective registry study in children, including dialysis and pre-dialysis patients, the geometric mean dose range was 1.4–2.0 mcg/kg/month (0.3–0.5 mcg/kg/week) [96].

Pharmacokinetics

One study evaluated the half-life of DA in pediatric patients with CKD [97]. Each patient received one dose of DA (0.5 mcg/kg) intravenously and subcutaneously. The half-life of DA with IV administration was 22.1 h (SD = 4.5 h). The half-life was 42.8 h (SD = 4.8 h) with subcutaneous administration. The pharmacokinetics were comparable to a similarly designed study in adults except for increased bioavailability (54% vs. 37%) and an earlier Tmax (36 h vs. 54 h) in the pediatric patients when DA was administered subcutaneously [97, 98]. Hence, DA may be absorbed more rapidly in pediatric patients [97]. More rapid absorption was also seen in pediatric studies of rHuEPO [99].

Dosing

Based on protein mass, 1 mcg of DA is equivalent to 200 units of rHuEPO. Nevertheless, the recommended DA dose by the manufacturer when converting patients from rHuEPO to DA is not a direct conversion based on the 1 mcg of DA to 200 units rHuEPO ratio (Table 59.6). The recommended conversion ratios are based on an analysis of the dose conversion clinical trials [100]. This analysis indicates that proportionally less DA was needed in patients who began the trial on higher doses of rHuEPO [100]. The explanation for this observation is unclear. It is possible that the efficacy of DA increases at higher doses. Alternatively, there may simply be a “regression to the mean” in those patients who were on very high doses of rHuEPO. These patients may have had a transient reason (e.g. inflammation) that led to high ESA dose requirements that subsequently resolved, allowing lowering of the DA dose during the study.

Table 59.6 Starting dose of darbepoetin alpha based on previous dosing of rHuEPO
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One challenge with DA administration in children is the lack of a multidose vial. First, many small pediatric patients are likely to need less than 25 μg, the smallest available single-dose vial. This results in wasting of the unused medication. Second, pediatric patients may not tolerate the discomfort of 1 mL injections or may require multiple injections in order to tolerate the full 1 mL volume of the single-dose vials. A useful alternative is to utilize DA in more concentrated single-dose prefilled syringes. Thus, dosing of DA necessitates knowledge of the available preparations (Table 59.7), and requires creative adjustments of doses and dosing intervals to minimize wasting of medication.

Table 59.7 Available preparations of darbepoetin alpha (single use vials)
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Table 59.8 Dose adjustment table for darbepoetin alpha
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Recommendations for converting patients from rHuEPO to DA based on adult data are available (Table 59.6). Patients who are receiving rHuEPO twice or thrice weekly should receive DA weekly, and patients who are receiving weekly rHuEPO should receive DA every other week.

Based on the pediatric literature, a reasonable starting dose of DA in ESA naïve patients is approximately 0.5 mcg/kg given weekly. Alternatively, the same total dose could be given every 2 weeks (i.e. 1 mcg/kg every 2 weeks). Every 2-week dosing at initiation should be reserved for patients with a Hb that is only mildly below target. Close monitoring of the Hb is essential for all patients due to the variable response to DA.

As occurs with rHuEPO, frequent dose adjustments of DA are often necessary [88]. Since DA has a long half-life, it is important not to increase the dose too quickly to avoid overshooting the target Hb. Many patients require lower doses after their Hb reaches the target range. When adjusting DA dosing, it is desirable to round doses based on the available preparations (Table 59.7) to avoid excessive wasting of the medication. Nevertheless, excessive rounding is not appropriate; some patients will need to discard some of their medication. Table 59–8 presents one system for dose adjustment. It is unclear whether the DA is evenly distributed in the prefilled syringes. Hence, gentle mixing of the medication and transfer to a 1 mL syringe has been recommended for patients who do not need a full dose [94].

Dose frequency of DA can be gradually reduced from weekly to every other week to every 3 weeks to every 4 weeks [101]. Not all patients will tolerate decreased dose frequency, especially beyond every 3 weeks. The dose frequency can be reduced whenever the patient has a Hb level that would normally mandate decreasing the dose. Alternatively, the dose frequency can be reduced in patients who are on a stable DA dose and have a Hb in the target range. The total weekly dose should remain the same. For patients receiving DA less often than weekly, consideration should be given to increasing the dose frequency if a patient requires more than 1 dose increase, especially if the total weekly dose is relatively high.

Complications

Side effect profiles have been similar in studies comparing IV DA with IV rHuEPO [88, 89]. In one study, there was a statistically significant increase in pruritus in the DA group [89]. Injection site pain is more severe in children with subcutaneous DA than with rHuEPO [102]. There have been cases of antibodies developing to DA leading to pure red cell aplasia [103].

Methoxy Polyethylene Glycol-Epoetin Beta

Methoxy PEG-epoetin beta is made by linking EPO with a large polymer chain via amide bonds between amino acids and methoxy PEG butanoic acid. Methoxy PEG-epoetin beta is also called Continuous Erythropoietin Receptor Activator (C.E.R.A.). A long half-life permits less frequent dosing [104].

Efficacy

A number of studies have demonstrated the effectiveness of methoxy PEG-epoetin beta in adult patients with CKD [105,106,107,108,109,110,111]. In a direct comparison with DA in adult HD patients, methoxy PEG-epoetin beta was superior at maintaining Hb at the prescribed target [112]. Methoxy PEG-epoetin beta given either every 2 weeks or every 4 weeks was comparable to rHuEPO in adult dialysis patients [107, 109].

Methoxy PEG-epoetin beta is effective in adult kidney transplant recipients [113, 114]. In a randomized study, once-monthly methoxy PEG-epoetin beta was compared with every 1–2 weeks DA, with similar efficacy and side effect profiles [115].

Two clinical trials have demonstrated that methoxy PEG-epoetin beta is effective in children with CKD [116, 117]. Children with stable anemia undergoing HD were converted from EPO or DA to methoxy PEG-epoetin beta, and Hb remained stable [116]. Similar efficacy was seen in a clinical trial that included children with pre-dialysis CKD and children receiving PD or HD [117].

Pharmacokinetics

The half-life of methoxy PEG-epoetin beta was 134 h and 139 h in adult PD patients following IV and subcutaneous dosing, respectively [118]. The peak reticulocyte count occurred at a mean of 8 days in both groups. Injection site location does not influence the pharmacokinetics, with half-lives between 160 and 164 h [104].

Dosing

For adults, the starting dose is 0.6 mcg/kg every 2 weeks, with conversion to monthly dosing once the Hb is within the target range. The every 2 week dose is doubled to calculate the monthly dose. An initial dose of 1.2 mcg/kg every 4 weeks was effective and comparable to DA every 1–2 weeks in a randomized clinical trial in ESA naïve non-dialysis patients [110]. In one study, the dose conversion ratio for HD patients converted from DA to methoxy PEG-epoetin beta was 1.21 mcg of methoxy PEG-epoetin beta for each 1 mcg of DA [119]. In a small study of pediatric kidney transplant recipients, the patients received a median dose of 2.5 mcg/kg every 4 weeks [120]. In a study of children 6–17 years receiving HD, a conversion factor of 4 mcg every four weeks of methoxy PEG-epoetin beta for each weekly dose of 125 U of EPO or 0.55 mcg of DA maintained a stable Hb [116]. In a registry study of patients receiving HD or PD, monthly doses per kg/month were much higher in younger children than older children, although the difference was minimal when analyzed using body surface area (approximately 100 mcg/m2/month) [121].

Methoxy PEG-epoetin beta is available in single use vials and single use prefilled syringes in a variety of doses. The prefilled syringes are more concentrated and hence preferable in patients who require subcutaneous injection.

Complications

In adult HD patients, conversion from DA to methoxy PEG-epoetin beta led to more transfusions [119]. No safety concerns have been noted in the pediatric studies [116, 121].

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors

Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHIs) have a different mechanism of action than the other ESAs, and they have the advantage of oral administration. HIF-PHIs activate the normal response to hypoxia. HIF-α is constitutively produced; however, in the absence of hypoxia, HIF-α is degraded via the actions of propyl hydroxylase domain (PHD) enzymes (PHD1, PHD2 and PHD3), which are oxygen sensors. These PHD enzymes hydroxylate proline residues in HIF-α, leading to ubiquitylation and proteasomal degradation of HIF-α [122, 123].

Hypoxia or HIF-PHIs decrease the degradation by PHD enzymes of HIF-α, which can then combine with HIF-β, and translocate to the nucleus, where the resulting heterodimer increases transcription of a variety of hypoxia-responsive genes, including EPO in kidney and liver cells, glycolytic enzymes, angiogenic factors, and proteins involved in iron metabolism, absorption, mobilization and transport [122, 123]. The induction of EPO in liver cells permits effective use in anephric patients, though it is unknown whether such patients will require higher doses.

Theoretically, HIF-PHIs could also increase Hb levels by increasing the availability of iron for red blood cell synthesis, especially in patients with decreased iron availability due to inflammatory blockade. HIF decreases synthesis of hepcidin, which is increased by inflammation and decreases iron availability for red blood cell synthesis. Moreover, HIF directly increases ferroprotein, which increases the release of absorbed and stored iron into the circulation, and transferrin, which transports iron to the bone marrow [122, 123].

There are multiple HIF-PHIs, including daprodustat, roxadustat, molidustat, vadadustat and enarodustat. They have different pharmacologic and pharmacodynamic properties [122, 123]. Roxadustat, daprodustat and enarodustat are primarily metabolized by cytochrome P450 enzymes, while molidustat and vadadustat are primarily metabolized by uridine 5′-diphospho-glucuronosyltransferases. Roxadustat is administered thrice weekly; the others are given daily [123].

The HIF-PHIs have been studied in pre-dialysis and dialysis-dependent adult patients. These studies demonstrate dose-dependent increases in Hb when compared to placebo, and generally equivalent hematologic responses when compared to other ESAs [122, 123]. There is not yet compelling evidence for a clinical benefit of HIF-PHIs on iron metabolism in patients with CKD (e.g. decreased need for IV iron). There is also a hope that patients with inflammation may respond better to HIF-PHIs than other ESAs. There remains concern regarding the multiple actions of HIF-PHIs beyond stimulating erythropoiesis could lead to adverse effects (e.g. upregulation of vascular endothelial growth factor could theoretically enhance tumor growth or worsen retinal disease), though there is also the possibility of beneficial effects (e.g. improved lipid metabolism). One study suggested a cardiovascular safety concern with vadadustat when compared to DA in non-dialysis-dependent adults with CKD [124]. Both positive and negative effects may differ by preparation [122, 123].

Monitoring Iron Stores

Serum ferritin and TSAT are the most widely used tests for monitoring iron stores. However, the United Kingdom National Institute for Health Care Excellence (NICE) guidelines recommend initiating iron therapy based on the measurement of either the percentage of hypochromic red blood cells (iron if >6% unless ferritin >800 mcg/L) or the reticulocyte Hb count (iron if <29 pg unless ferritin >800 mcg/L) [3, 125], though pediatric reference ranges may be needed [126, 127]. Per these guidelines, ferritin and TSAT should only be used if these tests are not available or the patient has thalassemia or thalassemia trait [3]. There is some information on the use of these measures in children, but studies are quite limited [128, 129]. Test availability remains a barrier in many settings, especially since samples may need to be processed relatively quickly (<6 h for percentage of hypochromic red blood cells).

Per KDIGO, TSAT and serum ferritin should be measured at initiation of ESA therapy in all children with CKD [1]. Subsequent monitoring should be at least every 3 months [1]. More frequent monitoring is appropriate in a variety of clinical situations, including after initiation of ESA therapy, when there is a poor response to ESA therapy, after a course of IV iron, or during administration of chronic IV iron therapy. Children receiving IV iron doses of more than 1.5 mg/kg or more than 100 mg should have a delay of at least 1 week before checking serum iron parameters.

Diagnosis of Iron Deficiency

The gold standard for diagnosing iron deficiency in patients with CKD is bone marrow assessment of iron stores, a test that is impractical on a routine basis. An alternative definition is the response to IV iron. An increase in Hb or a decrease in ESA dose after receiving IV iron suggests that the patient was iron deficient. This definition is not perfect—the “response” to IV iron may be coincidental or the patient may not respond for other reasons—but it has been widely used in clinical research and clinical practice.

The traditional criterion for iron deficiency, the combination of a low serum ferritin and a low TSAT, are not applicable in patients with CKD. The serum ferritin is especially problematic because ferritin is an acute phase reactant, and it is therefore often elevated in CKD patients because of infection and non-specific inflammation. Moreover, treatment with an ESA can induce functional iron deficiency. This occurs because the high rate of red blood cell synthesis depletes the readily available iron, even though total body iron stores may be adequate. Patients with functional iron deficiency due to rapid erythropoiesis may have a normal ferritin, but a low TSAT. Often the ferritin level decreases in these patients, yet it remains in the normal range, and it is therefore not as useful a predictor of iron deficiency as the TSAT.

A TSAT below 20% and a serum ferritin below 100 ng/mL is consistent with an absolute iron deficiency. A TSAT below 20% and a serum ferritin above 100 ng/mL suggests a functional iron deficiency. This same scenario can also occur with an inflammatory block, a condition where inflammation prevents effective delivery of iron for erythropoiesis. Clinical signs of infection, a low serum iron, an elevated CRP, and an increasing ferritin support a diagnosis of an inflammatory block.

KDIGO recommends treating adult CKD patients with IV iron when the TSAT is <30% and the ferritin is <500 ng/mL, assuming there is an indication (desire to increase the Hb or decrease the ESA dose). It is clear that some patients respond to IV iron despite an elevated ferritin [130]. This has led to controversy regarding the upper limit of ferritin in the KDIGO guidelines, with some suggesting that there is no evidence base for an upper limit for ferritin of 500 ng/mL [72, 73]. There has been an increase in the use of IV iron worldwide [131], and in the US the mean serum ferritin in HD patients increased to close to 800 ng/ml [71].

The KDIGO cutoffs for initiating IV iron in pediatric patients are a TSAT <20% and a ferritin <100 ng/ml. This is quite conservative and many pediatric nephrologists treat patients with TSATs <20–30% despite ferritin values >100 ng/ml. The upper limit of ferritin for holding IV iron for pediatric patients varies among clinicians, with some practitioners using cutoffs of 500–800 ng/ml. This variation is due to the lack of evidence supporting a specific cutoff.

Iron Therapy

After EPO deficiency, iron deficiency is the leading cause of anemia in children with CKD. Treatment of iron deficiency often allows achievement of the target Hb with a lower dose of ESA. Iron therapy should not be given to patients who have iron overload, which is commonly defined as a ferritin greater than 800 ng/mL or a TSAT>50%.

Oral Iron

Only a small percentage of oral iron is absorbed, limiting its efficacy in patients who have high iron requirements due to blood loss, such as children receiving HD [9]. Adherence to therapy may be problematic due to problems with gastrointestinal side effects, including abdominal discomfort and constipation [132]. In HD patients, oral iron appears to be of limited benefit and is poorly tolerated [133].

There is an up-regulation in oral iron absorption in patients who have a low serum ferritin or decreased marrow iron stores. However, HD patients have decreased absorption of oral iron when compared to normal controls; inflammation, which is common in HD patients, decreases iron absorption. This is partially mediated by hepcidin, which inhibits iron absorption from the intestines, and is increased by inflammation [22].

Oral iron absorption is decreased when given with food; hence, iron should be given either 1 h before or 2 h after a meal. Calcium carbonate and calcium acetate decrease iron absorption; oral iron should not be given at the same time as these phosphate binders. Sevelamer seems to have little effect on oral iron absorption [134]. H2-receptor antagonists and proton pump inhibitors may also adversely affect iron absorption.

Oral iron may be adequate therapy in children who are not receiving HD. In children receiving HD, oral iron is often not sufficient to correct absolute or functional iron deficiency [135, 136]. Children receiving chronic IV iron should not receive oral iron given the limited benefits and high rate of side effects of oral iron.

Ferrous sulfate, an iron salt, is the most commonly prescribed oral iron preparation; other iron salts include ferrous fumarate, ferrous gluconate and polysaccharide iron complex. Iron salts rapidly release iron ions, which increases the risk of gastrointestinal side effects. The iron salts are inexpensive options. Children should receive a dose of 3–6 mg/kg/day of elemental iron (maximum dose: 150–300 mg/day).

There are a variety of alternative options to iron salts, but many are expensive, with prices that range from 20 to more than 500 times the cost of ferrous sulfate. The possible advantages include increased effectiveness due to increased bioavailability, and improved tolerability with some preparations.

Ferric citrate was originally approved as a phosphate binder, but has been shown to be effective in treating iron deficiency, though gastrointestinal side effects are common [137,138,139]. In a randomized study in adults with CKD, ferric citrate was superior to ferrous sulfate for correcting iron deficiency [140]. There is limited pediatric experience with ferric citrate as a phosphate binder [141].

Ferric maltol is an oral iron preparation that was approved by the FDA and European Medical Agency for iron deficiency based on studies of patients with inflammatory bowel disease and CKD [142, 143]. It is better tolerated than iron salts [142]. Because of its improved bioavailability, doses of 30 mg twice daily are effective in adults. A randomized study in adult inflammatory bowel disease patients showed comparable 26 and 52 week efficacy when compared to IV ferric carboxymaltose [144]. There is no published pediatric experience.

Sucrosomial® iron has improved bioavailability and gastrointestinal tolerance compared to iron salts [144]. It is effective in adults with CKD at a dose of 30 mg daily, and had comparative long-term efficacy in increasing hemoglobin in adult CKD patients not on dialysis when compared to 125 mg of IV iron gluconate given weekly, though iron stores improved more with IV iron gluconate [145]. It is much less expensive than the other alternatives to iron salts (ferric citrate and ferric maltol) and is cost-effective when compared to IV iron preparations [146]. It is available over the counter in the US, though only via on-line sources. There is no published pediatric experience.

Intravenous Iron

IV iron is more effective than oral iron in correcting anemia in adult patients with CKD, although the benefit is relatively small in pre-dialysis patients [132, 147, 148]. IV iron is believed to be cost effective in HD patients due to decrease ESA utilization [149, 150]. Studies in children, including a meta-analysis [151], have shown the efficacy of IV iron in correcting iron deficiency, improving Hb levels, and reducing rHuEPO dose requirements [135, 136, 152,153,154,155]. There is limited experience using IV iron in pediatric kidney transplant recipients [156].

Acute dosing of IV iron is used for patients who have evidence of iron deficiency, which is most commonly defined based on measures of iron stores. The dose given is relatively large. Chronic dosing utilizes smaller doses to maintain iron stores and provide a regular source of iron for erythropoiesis. Acute dosing results in a more significant change in Hb and iron stores [157]. For children receiving PD or who are predialysis, the goal is usually to minimize the need for IV line placement by maximizing the dose given during a single infusion. A chronic dosing strategy is generally only utilized in patients receiving HD due to the burden of IV placement.

Preparations

There are a variety of IV iron preparations available (Table 59.9). The European Pediatric PD Working Group recommended not using iron dextran due to concerns about life-threatening anaphylactic reactions [30]. These preparations have different side effect profiles. In addition, there is no preparation that is ideal in every situation. Iron sucrose and ferric gluconate have limitations on individual doses and must be given over an extended period when higher doses are utilized. This somewhat limits their utility in patients who are not receiving HD. In contrast, ferric carboxymaltose, ferric derisomaltose and ferumoxytol can be given more rapidly at higher doses. However, ferric carboxymaltose, ferric derisomaltose and ferumoxytol are not designed to be given in a chronic dosing strategy due to product packaging in very high doses.

Table 59.9 Intravenous iron preparationsa
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Ferric gluconate is generally well-tolerated [158, 159], and an effective treatment for CKD patients with iron deficiency [130, 160,161,162,163]. Ferric gluconate is available in 62.5 mg vials. Acute dosing in adult HD patients is typically 125 mg administered over 10 min given over 8 consecutive HD sessions (total dose = 1000 mg). The recommended acute dose in children receiving HD is a maximum of 1.5 mg/kg over 10 min. In adults, ferric gluconate doses of 250 mg, over 60 or 90 min, were well tolerated [164], as were infusions over 1–4 h) [165]. In children, one study reported administration of doses ranging from 1.5 to 8.8 mg/kg, with the child receiving the highest dose having a significant adverse event [152]. Thus, acute doses of ferric gluconate in patients not receiving HD should not exceed 4 mg/kg (250 mg if >60 kg), which should be given over at least 90 min.

Iron sucrose is generally well-tolerated [166, 167] and effective in correcting iron deficiency in patients with CKD [168,169,170]. Iron sucrose is available in 50 mg vials. Adult HD patients are usually given 50 or 100 mg over 5 min [166]. Infusions of 100 mg over 10 consecutive dialysis sessions is used for acute dosing to provide a total of 1000 mg. For chronic dosing in adult HD patients, doses of 50 or 100 mg avoids wasting medication and can be given weekly or every other week [166].

In adult PD or predialysis pat over 1.5–2 h, appear to be well tolerated. Doses of iron sucrose as high as 500 mg have been given, but the infusion time must be extended to avoid side effects, and this dose may not be tolerated in smaller adults [169, 171, 172]. In children, a dose of 2 mg/kg (maximum 100 mg) over 3 min or 5 mg/kg (maximum 300 mg) over 90 min is well-tolerated [173]. The 5 mg/kg dose can be repeated the next day [173].

Ferric carboxymaltose is effective in treating iron deficiency and is approved for use in non-dialysis CKD patients [175,176,177,178,178]. When ferric carboxymaltose was directly compared to iron sucrose, there was more hypertension in the ferric carboxymaltose group and more hypotension in the iron sucrose group [177]. There are recommendations for acute dosing in adults: 15 mg/kg (maximum 750 mg) with a second dose at least 1 week later. It is administered over 15 min. There is substantial pediatric experience with ferric carboxymaltose, but limited experience in children with CKD [180,181,182,183,183]. In one study, the usual dose was 15 mg/kg, with a maximum dose of 750 mg [179]. In another study, the usual dose was 20 mg/kg, with a maximum dose of 1000 mg in children >35 kg and 500 mg in children <35 kg [183]. Ferric carboxymaltose is available in 750 mg vials, precluding its use in a chronic dosing strategy (see below) or in small children without wasting medication. Hypophosphatemia is a complication in adults with CKD and children who receive ferric carboxymaltose for other indications [177, 185,186,187,187].

Ferumoxytol, approved for CKD patients, is effective when given to adults at a dose of 510 mg, followed by a second dose 3–8 days later, though single doses of 1020 mg also appear safe [189,190,191,191]. The infusion rate should not exceed 30 mg of iron/second. The large vial size (510 mg) limits its utility in small children or for use in a chronic dosing strategy. There is limited pediatric experience, albeit not in children with CKD [192, 193]. In one study, ferumoxytol at a dose of 10 mg/kg (maximum 510 mg) was administered over 60 min and 15 min for the first infusion and subsequent infusions, respectively [193].

Ferric derisomaltose is approved and marketed in more than 30 countries worldwide, including the US, the EU, Canada, and Australia for treating iron deficiency. It has comparative efficacy to iron sucrose in patients without CKD and patients with pre-dialysis CKD. There is no published pediatric experience [194, 195].

Acute Dosing

Acute doses of IV iron are given when the patient has evidence of iron deficiency (see criteria above). The goal of acute IV iron dosing is to normalize the serum ferritin and the TSAT. In some cases, an acute dose may be used as a trial of IV iron in a patient with normal iron studies, but a poor response to an ESA. In these patients, the goal of acute IV iron is a reduction in ESA dose or correction of resistant anemia.

In adult HD patients, studies suggest that a total dose of 1000 mg of iron, divided over multiple consecutive dialysis sessions, is appropriate, since smaller doses are not as effective [162]. A total dose of 1000 mg has been used in older children with good results [136]. A randomized study of children receiving HD compared 2 acute dosing regimens of ferric gluconate (1.5 mg/kg/dose and 3.0 mg/kg/dose; maximum dose, 125 mg/dose) given during 8 consecutive HD sessions. The patients had a TSAT <20% and/or a ferritin less than 100 ng/mL at baseline. Both doses led to an increase in Hb and normalization of iron indices. Since there was no difference in the response, the authors recommended a dose of 1.5 mg/kg/dose (maximum of 125 mg/dose) for 8 consecutive HD sessions [196]. This provides a total dose of 12 mg/kg (maximum dose of 1000 mg). Based on the available evidence, the total dose for acute pediatric dosing should be between 12 and 25 mg/kg (1000 mg maximum) divided over up to 12 HD sessions, depending on the dose and iron preparation (see above discussion of specific preparations).

Chronic Dosing

Acute dosing is effective in correcting iron deficiency, but especially in HD patients there is a risk of ongoing episodes of iron deficiency due to continued blood loss. Transient iron deficiency may lead to decreased red blood cell synthesis. This has led to more frequent chronic IV iron use. Observational studies in adults suggests that maintenance therapy may be associated with better outcomes than an acute dosing strategy [197, 198].

In one pediatric study, 1 mg/kg of ferric gluconate for 12 weeks led to a significant increase in Hb [135]. In another pediatric study, chronic IV iron sucrose (2 mg/kg [max = 200 mg] weekly) produced a reduction in rHuEPO dose [153]. A randomized 16-week study in children receiving HD compared maintenance IV iron dextran (doses of 25, 50 or 100 mg/week based on weight; doses therefore ranged from 1.25–2.5 mg/kg/week) with oral iron (4–6 mg/kg/day). The patients receiving IV iron had a significant increase in ferritin when compared to the oral iron group. There was a trend toward a reduction in rHuEPO dose in the IV iron group when compared to the oral iron group [155].

Another study randomized children receiving HD to intermittent IV iron versus maintenance IV iron. There was a higher rate of iron overload in the children receiving intermittent IV iron [199]. This observation may be secondary to a decreased ability to utilize stored iron in children receiving HD due to an inflammatory block. The low doses of maintenance IV iron are immediately employed for red cell synthesis, avoiding an excessive accumulation of stored iron. This contrasts with intermittent IV iron; the high doses cannot all be utilized immediately, increasing the risk of eventual iron overload.

One pediatric study prospectively followed children who were started on a maintenance dose of 1 mg/kg/week of ferric gluconate and then adjusted the dose of ferric gluconate based on iron studies. The majority of the patients completing the study required a dose of 1.5 mg/kg to maintain adequate iron stores [200].

Maintenance IV iron in children receiving HD should be started at about 1 mg/kg/week, usually given as a once/week dose. The maintenance dose is titrated to keep the TSAT above 20% and the ferritin above 100 ng/mL; IV iron should be held if the TSAT is greater than 50% or the ferritin is greater than 500 ng/mL.

Complications

There are some complications of IV iron that are specific to the particular preparation. Iron dextran may cause an acute anaphylactic reaction, which is potentially fatal [201]. Iron sucrose [159] and ferric gluconate [162] have a safer side effect profile, although all IV iron preparations have the potential to cause serious adverse reactions. Children and adults who have had anaphylactic reactions to iron dextran have tolerated other iron preparations [152, 202, 203]. High doses of iron dextran may cause patients to develop arthralgias and myalgias [204].

There are reports of laboratory findings and clinical symptoms that may be due to acute iron toxicity during the use of iron sucrose and ferric gluconate. This effect is related to the dose and infusion rate and is presumably secondary to rapid release of free iron. Symptoms with ferric gluconate have included loin pain, hypotension, emesis and paresthesias [205]. Iron sucrose side effects have included rash, flushing, and hypotension, which were rapidly reversible [206]. These side effects limit the maximum single dose of these compounds when compared to iron dextran, which releases free iron at a slower rate.

Use of IV iron may increase generation of reactive oxidative species, which has the potential to impair endothelial cell function, promote atherosclerosis, cause inflammation, and decrease immune function [208,209,210,210]. There is evidence of an association between higher iron dose and increased adverse outcomes, recognizing a variety of potential confounders [211]. These adverse events may be less likely with iron preparations that release iron more gradually (e.g. ferric carboxymaltose, ferumoxytol and ferric derisomaltose) than iron sucrose or ferric gluconate. This was seen in a randomized study comparing iron sucrose with ferumoxytol [177]. Yet, there is not yet enough evidence to reach a conclusion on this issue given the limitations with the extant literature [212].

Ferumoxytol is associated with higher rates of adverse events than iron sucrose or ferric gluconate [167]. Adverse reactions include injection site reactions, hypersensitivity reactions and hypotension that can be severe [213]. Patients should be observed for at least 30 min after receiving ferumoxytol. Its use may also transiently affect MRI interpretation since it is also used as a contrast agent for MRIs [213].

Iron overload is a potential complication of IV iron therapy, and may occur in CKD patients receiving IV iron [215,216,216]. There is concern that current IV iron protocols may lead to more problems with iron overload, which has been seen in children receiving acute or maintenance IV iron [153, 199].

IV iron may cause hypophosphatemia, which appears to be mediated by increased levels of FGF-23 and urinary phosphate wasting [217, 218]. Clinically significant, sustained hypophosphatemia is associated with ferric carboxymaltose [186, 187, 219].

IV iron may increase the risk of infection [220]. A multivariate analysis did not find a relationship between IV iron and infection, although there was a trend toward more infections among those patients who received large amounts of IV iron versus those who received lower doses [221]. Given this potential complication, IV iron should be held in patients with acute infections.